Regulation of hepatic gene expression by Kupffer cell-derived mediators

Kupffer cells are major producers of inflammatory mediators in the liver. T hey include cytokines, growth factors, and lipid and inorganic metabolites. Tumor necrosis factor-alpha (TNF-alpha) is one of the best characterized c ytokines. Besides its proinflammatory action, TNF-alpha triggers proliferat ion of hepatocytes by activating NF-kappa B, leading to interleukin 6 (IL-6 )-dependent STAT 3 activation and immediate early gene response, Anti-apopt otic action of TNF relating to the activation of NF-kappa B, c-Jun NH2-term inal kinase, and p38 kinase might also be involved in this process. In cont rast, TNF-alpha induces apoptosis of hepatocytes in some restricted conditi ons. Nitric oxide (NO) generated by inducibe NO synthase in Kupffer cells and he patocytes is similarly either harmful or protective to hepatocytes. IL-18, initially called as interferon-gamma (IFN-gamma-inducing factor (IGIF), is a novel cytokine produced dominantly by Kupffer cells. IL-18 upregulates na tural killer (NK) activity and IFN-gamma production in liver specific NK ce lls, pit cells. In particular, IL-18 plays important roles in the apoptosis of hepatocytes through upregulating Fas ligand expression in liver NK cell s. On the other hand, Kupffer cells synthesize fibrogenic growth factors su ch as platelet-derived growth factor (PDGF) and transforming growth factor- beta (TGF-beta). PDGF triggers proliferation and migration of stellate cell s via activating multiple signaling cascade. In addition, PDGF prompts cell cycle of stellate cells by inducing G1 cyclins. TGF-beta induces collagen gene expression and negatively regulates cell cycle of liver cells. Thus, K upffer cell-derived mediators modulate gene expression of hepatic-constitue nt cells and may play crucial roles in local inflammatory reactions.